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    Home > Medical News > Latest Medical News > ADC: The "Magic Bullet" Road to Innovation

    ADC: The "Magic Bullet" Road to Innovation

    • Last Update: 2022-03-05
    • Source: Internet
    • Author: User
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    TextTruth-seeking Mission

    01

    01

    Origin: Two types of therapy, integration of advantages

    Origin: Two types of therapy, integration of advantages

    The two major treatment strategies for clinical cancer treatment are antibody-based immunotherapy and chemical drug-based chemotherapy.


    Chemotherapy includes antitumor antibiotics such as doxorubicin that interfere with transcription by directly destroying DNA or intercalating DNA, alkylating agents such as nitrogen mustard that inhibit tumor proliferation, and antibody metabolizing agents such as methotrexate;

    Immunotherapy includes five categories of therapies: targeted antibodies, adoptive cell therapy, oncolytic viruses, cancer vaccines, and immunomodulators.


    But both types of mainstream therapy have flaws determined by their characteristics.


    Figure 1.


    In the chemotherapy treatment system, although small-molecule chemical drugs have a high killing effect on cancer cells, they have poor selectivity, almost indiscriminately attack normal cells and tumor cells, and have serious negative effects.


    Therefore, in order to solve the shortcomings of the two mainstream cancer therapies, the researchers imagined whether the high-efficiency killing of chemotherapy could be combined with the precise targeting of immunotherapy


    Figure 2.


    Under the guidance of this idea, the antibody-drug conjugate (ADC) is to link the biologically active small molecule drug to the monoclonal antibody through a chemical link, and the monoclonal antibody acts as a carrier to transport the small molecule drug in a targeted manner.


    02

    02

    Development History: Three Stages, Three Generations of Drugs

    Development History: Three Stages, Three Generations of Drugs

    Figure 3.


    1

    1

    The budding stage (1910-1980)

    The budding stage (1910-1980)

    Paul Ehrlich began with the idea of ​​a cure for syphilis, first coining the concept of the "magic bullet" in 1913


    2

    2

    Exploring Stage (1980-2000)

    Exploring Stage (1980-2000)

    Among the first-generation ADC drugs, antitumor drugs such as mitomycin C and vinca alkaloids are mainly coupled with mouse monoclonal antibodies through non-cleavable linkers (amide or succinimide), and there are serious immunogens Sexual issues


    Figure 4.


    3

    3

    Mature stage (2000-present)

    Mature stage (2000-present)

    The second-generation ADC representative drugs are Adcetris (Seattle Genetics) launched in 2011 and Kadcyla (Roche) launched in 2013, using humanized monoclonal antibodies represented by trastuzumab and more efficient small molecule drugs, Together to drive the upgrade iteration of ADC technology


    However, the coupling method is still similar to the first generation, and the stability of the linker still needs to be improved


    Figure 5.


    The research is never-ending, and soon the third generation ADC drugs enter people's field of vision


    Figure 6.
    Characteristics of third-generation ADC drugs, source: Nature, Ping An Securities Research Institute

    There are currently 13 ADC drugs on the market in the world.
    The treatment areas are mainly focused on hematological tumors and solid tumors, and they are mainly used for the late-line treatment of patients, including advanced, relapsed/refractory and metastatic tumor indications.
    It is expected to continue to be a research hotspot in the field of anticancer in the next few years
    .

    03

    03

    Technical principle: five cores, precise function

    Technical principle: five cores, precise function

    Simply put, ADC is a combination therapy of "monoclonal antibody + chemotherapy", and ADC drug is a combination of three elements of "antibody + linker + effector molecule", thus taking into account the selective characteristics of monoclonal antibodies and the killing ability of chemotherapy
    .

    1

    1

    ADC drug mechanism of action

    ADC drug mechanism of action

    ADC first enters the blood circulation through intravenous injection, and the antibody recognizes and binds to the specific antigen on the cell surface
    .
    Then, under the mediation of cell surface receptors that specifically bind to cell surface antibodies, the ADC drug is endocytosed and entered into lysosomes for degradation, and the effector is released in a sufficient amount in the cell in a highly active form to play a role.
    Directly kills or induces apoptosis
    .

    Figure 7.
    ADC drug mechanism of action, source: Antibody–drug conjugates as novel anti-cancer chemotherapeutics

    2

    2

    Five core technologies

    Five core technologies

    Therefore, in terms of mechanism of action, target selection, antibody modification, Linker design, selection of toxic small molecules, and coupling methods have become the five core factors affecting ADC drug design
    .

    1) The choice of target

    1) The choice of target

    Target is one of the important factors in determining ADC indications and is the basis for ADC design
    .
    To become a target, the following conditions must be met, that is, high expression in tumor cells and low expression in ordinary cells, localization on the cell surface, and internalization function
    .
    The three are indispensable, and they are the guarantee of ADC's precise function, full contact, and full function inside the cell
    .

    Figure 8.
    ADC targets, source: Xiangcai Securities

    2) Antibody modification

    2) Antibody modification

    There are five main classes of antibodies: IgM, IgD, IgG, IgE and IgA
    .
    Among them, IgG1, a subtype of IgG, is the most commonly used antibody for cancer immunotherapy
    .
    A typical IgG1 antibody consists of two heavy chains and two light chains, and is divided into two regions
    .
    The Fc region is responsible for antibody recognition by immune effectors; the Fab region is responsible for providing antigen specificity
    .

    Figure 9.
    IgG1 antibody, source: Seattle Genetics

    Why does the IgG1 scaffold stand out?

    From the table data comparison, it can be seen that IgG1 has relatively strong antibody-dependent cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) and is easy to produce
    .
    And long half-life, it is an ideal choice for ADC drugs
    .

    Figure 10.
    Comparison of four subtypes of IgG, source: Xiangcai Securities

    3) Linker's design

    3) Linker's design

    Typically, linker design requirements require both stability and the ability to release effectors when they reach an appropriate location
    .
    Linkers are divided into cuttable and non-cuttable types:

    Cuttable linker:

    The linker mainly takes advantage of the environmental differences between the blood system and tumor cells.
    When the environment changes, the linker breaks and releases the drug; splittable linkers can be divided into three main subclasses: acid-dependent bond breaking, redox-dependent breaking bonds and enzymatically cleavable bonds
    .

    Uncut linker:

    The linker is more stable in plasma, and there is evidence that the release of the linker payload occurs mainly in lysosomes after ADC internalization, with low systemic toxicity
    .

    4) Selection of toxic small molecules

    4) Selection of toxic small molecules

    As the key to the lethality of ADC, there are two main mechanisms: one is to cause DNA damage; the other is to inhibit tubulin multimerization
    .
    It has the characteristics of strong toxicity, good water solubility and stability, and a group that can be coupled with linker
    .

    Figure 11.
    Toxic small molecules, source: Xiangcai Securities

    5) Coupling method

    5) Coupling method

    The early ADC random coupling method has many drawbacks, and the fixed-point coupling has gradually developed into a mainstream technology, mainly in the following four categories:

    a.
    Introduction of reactive cysteine

    a.
    Introduction of reactive cysteine

    Through genetic engineering, cysteine ​​residues are inserted at specific points of the antibody, and then the hydroxyl group on the cysteine ​​is coupled to the toxin to form a site-specific antibody-drug conjugate
    .

    Figure 12.
    Introduction of reactive cysteine, source: ADC Drug Research Report of Bioproducts Circle

    b.
    Introducing unnatural amino acids

    b.
    Introducing unnatural amino acids

    Unnatural amino acids are introduced into specific sites of any target protein in the organism, and the residues on these unnatural amino acids can be combined with linkers to form site-specific ADCs
    .

    Figure 13.
    Introduction of unnatural amino acids, source: ADC drug research report in biological product circle

    c.
    Enzymatic catalysis

    c.
    Enzymatic catalysis

    By inserting specific amino acid markers into the antibody sequence that can be recognized by some specialized enzymes, toxins can be selectively linked to antibodies
    .

    Figure 14.
    Enzymatic catalysis method, source: ADC drug research report of biological products circle

    d.
    Disulfide bond reduction method

    d.
    Disulfide bond reduction method

    By reducing the disulfide bond of the mAb itself, a dibromo reagent is used to react with the reduced interchain disulfide to provide a re-bridged mAb
    .

    Figure 15.
    Disulfide bond reduction method, source: ADC drug research report in the biological product circle

    04

    04

    Research Status: Five Advantages, Multifaceted Challenges

    Research Status: Five Advantages, Multifaceted Challenges

    1

    1

    Technical advantages

    Technical advantages

    As a relatively advanced and mature targeted drug technology in current anti-cancer therapy, ADC drugs show advantages in many aspects:

    1) Strong therapeutic efficacy:

    1) Strong therapeutic efficacy:

    The bystander effect exerts a good lethality, and multiple targets show the potential of pan-cancer therapy
    .

    2) The specific identification of the manslaughter rate is low:

    2) The specific identification of the manslaughter rate is low:

    The drug is directly delivered to the target site with high targeting
    .

    3) Weak immunogenicity:

    3) Weak immunogenicity:

    Most of the humanized vectors are used, which is not easy to produce drug resistance
    .

    4) The action cycle time is long:

    4) The action cycle time is long:

    Prolonged duration of action in serum
    .

    5) Low toxicity and side effects:

    5) Low toxicity and side effects:

    It has low toxicity to non-target cells and a high safe therapeutic window
    .

    2

    2

    face the challenge

    face the challenge

    ADC drugs are still in a stage of vigorous development as a whole, and they are facing huge challenges both in the research and development process and in clinical application
    .

    Off-target toxicity: Due to the difficulty of avoiding off-target during delivery, toxic small molecules will be released into the blood circulation in advance, causing the risk of poisoning
    .

    Figure 16.
    Off-target toxicity for some targets

    Protein aggregation: a major hurdle in ADC development
    .
    Repeated freezing and thawing and changes in temperature, concentration and pH may cause structural changes in ADCs to induce protein aggregation, thereby affecting immunogenicity and product loss
    .

    Drug resistance: The drug resistance of ADC drugs is related to the down-regulation of target antigens, cell cycle, signaling pathways, and gene mutations
    .

    Figure 17.
    Resistance mechanisms of ADC drugs, source: Biomedicines.
    2021 Aug; 9(8): 872.

    Clinical adverse reactions: In the clinical trials of ADC drugs, various adverse reactions have occurred, which are related to various factors such as the nature of the target, the selection of the linker, and the number of toxic carriers.

    Figure 18.
    Clinical adverse reactions of ADC drugs, source: "Expert Consensus on Clinical Application of Antibody Drug Conjugates in the Treatment of Malignant Tumors (2020 Edition)"

    05

    05

    Market and Prospects of ADC Technology

    Market and Prospects of ADC Technology

    1

    1

    market

    market

    1.
    Today, the research and development of ADC drugs is in a state of blowout, and the number of related patents, research and development projects and clinical drug experiments are all showing an upward trend
    .

    Figure 19.
    Global ADC drug patent applications from 1987 to 2018, source: China Securities

    2.
    Its future market expectations also show a high development trend
    .
    According to data model estimates, the global ADC drug market is huge, with total sales exceeding $16.
    4 billion by 2026
    .

    Figure 20.
    Global ADC drug sales market forecast in 2019-2026, source: Nature Reviews Drug Discovery

    2

    2

    R & D prospects

    R & D prospects

    1.
    Diversified targets

    1.
    Diversified targets

    At present, there has been a high repetition of target selection in ADC research and development, and most drugs are concentrated on a few popular targets, especially the HER2 target drugs under development far outnumber others
    .
    But in fact, there are more than 200 targets under research and development in the world, the choices are very diverse, and the potential of the targets needs to be further explored
    .

    Figure 21.
    Key distribution targets of ADC drugs under research and marketed globally, source: CITIC Construction Investment Securities

    2.
    Re-selection of indications

    2.
    Re-selection of indications

    In terms of indications, ADC drugs are highly concentrated in the field of disease research and are basically oriented towards solid tumors
    .
    However, relevant studies have shown that ADC drugs have great potential for non-cancer indications, and they have found medicinal power in autoimmune diseases, bacterial infections, liver fibrosis, viral infections, etc.
    , which opens up new directions for their research and development
    .

    references:

    [1] ADCs inspire large pharma investments.
    [J].
    Nature reviews.
    Drug discovery, 2020
    .

    [2] Peters C , Brown S .
    Antibody-drug conjugates as novel anti-cancer chemotherapeutics[J].
    Bioscience Reports, 2015, 35(4).

    [3] Diamantis N, Banerji U.
    Antibody-drug conjugates—an emerging class of cancer treatment[J].
    British journal of cancer, 2016, 114(4): 362-367.

    [4]Seattle Genetics Inc.
    v.
    Österreichisches Patentamt Regulation (EC) No 469/2009, 13 A.
    “Seattle Genetics” [J].
    IIC-International Review of Intellectual Property&Competition Law, 2016.

    [5]Dan N .
    Antibody-Drug Conjugates for Cancer Therapy: Chemistry to Clinical Implications[J].
    Pharmaceuticals, 2018, 11(2):32-.

    [6]Mckertish CM, Kayser V.
    Advances and Limitations of Antibody Drug Conjugates for Cancer.
    Biomedicines.
    2021 Jul 23;9(8):872.
    doi: 10.
    3390/biomedicines9080872.
    PMID: 34440076; PMCID: PMC8389690.

    [7] Professional Committee of Clinical Research on Cancer Drugs of China Anti-Cancer Association, National Expert Committee of Clinical Application Monitoring of Anti-tumor Drugs, Expert Committee of Breast Cancer of National Cancer Quality Control Center.
    etc.
    Expert consensus on clinical application of antibody-drug conjugates in the treatment of malignant tumors[J] ].
    Chinese Journal of Oncology, 2021, 43(1):78-91.
    DOI:10.
    3760/cma.
    j.
    cn112152-20201112-00981.

    [8]do Pazo C, Nawaz K, Webster RM.
    The oncology market for antibody-drug conjugates.
    Nat Rev Drug Discov.
    2021 Aug;20(8):583-584.
    doi: 10.
    1038/d41573-021-00054-2 .
    PMID: 33762691.

    [9] Ping An Securities.
    In-depth report on the biopharmaceutical industry: Special topic series on innovative drug research and development: ADC: the path from imitation to innovation

    [10] Caitong Securities.
    Special Report on Antibody Conjugated Drug ADC of Pharmaceutical Biotechnology

    [11] https://weibo.
    com/ttarticle/p/show?id=2309404405874675286019

    [12] https://zhuanlan.
    zhihu.
    com/p/69903303

    [13] https://zhuanlan.
    zhihu.
    com/p/266669469

    [14] https://zhuanlan.
    zhihu.
    com/p/371400304

    [15] https://broadpharm.
    com/web/products.
    php?category1=adc-linkers

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